Oral pharmaceutical composition for



Chester John Cavallito and Thomas Beniah ODell, De I catur, llL, assignors to Irwin, Neisler and (Zompany, Decatur, 11]., a corporation of Illinois No Drawing. Application August 20,1956

Serial No. 605,199

3 Claims. (Cl. 167-'55) "This invention relates to pharmaceutical compositions containing a physiologically active quaternary ammonium salt and is more particularly concerned with an improvenient in such compositions whereby the therapeutic effect of the active quaternary salt therein can be realized upon the oral administration of the composition.

The relatively poor absorption rate into the blood stream from the gastro-intestinal tract of quaternary salts having useful therapeutic properties has materially reduced the scope of their application since injection therapy necessarily requires professional administration as opposed tosimple oral therapy following the instructions of a physician.

.The present invention resides in the concept of a composition containing a therapeutically active quaternary ammonium salt'in combination with a therapeutically inactive quaternary ammonium salt. Excipients permitting proper dosage requirements and imparting pharmaceutical elegance are employed in compounding the finished preparation in a form suitable for dispensing.

The theory upon which the invention rests,.as best understood on the basis of extensive investigation, appears to be as follows: absorption of quaternary salts from the gastro-intestinal tract is mediocre because such salts become tightly bound to anionic receptors in the wall of the tract and, as a result, are not readily absorbed. For example, the mucins which form part of the lining of the intestinal tract are polysaccharide acids which apparently retain quaternaries by ionic attraction. The administration of a quaternary having no physiological activity, but having certain structural molecular properties in common with the active agent, in combination therewith, results in-the binding of the inactive quaternary at'many of the anionic sites in the wall of the intestine, leaving fewer of such sites available for binding of the therapeutic quaternaries.

The invention will be illustrated by reference to the administration of hypotensive agents, of which a number have been developed in the recent past. In'varying degree these are therapeutically useful by injectiontherapy, but absorption by the oral route is generally insufiicient to permit administration in practical or economical. dosage form.

Accordingly, we have compounded simple bis-quater-- nary ammonium alkanes whichare relatively inert biologically with bis-quaternary ammonium compounds having known therapeutically desirable hypotensive activity by the injection route and obtained entirely satisfactory re sults upon clinical evaluation. In general, the amount of the active hypotensive quaternary can be varied from about 25 to about 400 milligrams per dose and the amount of the relatively inactive quaternary employed should be between about 0.5 and about 3.0 milligrams per milligram of the active component in each dose. Above the ratio of about 3.0 parts of inactive quaternary per part of hypotensive quaternary, little advantage is apparent. The composition is preferably tabletted or capsulated in a manner following usual pharmacy prac- States Patent 9 ticebecause the taste of the quaternaries lessens the desirability of use in solution form. The'potentiating quaternaries are the bis-quaternaries of C through C ditertiaryaminoalkanes wherein the tertiaryamino-forming substituents are lower-aliphatic radicals, such as C through C lower-alkyl groups, which can be joined to form a saturated or unsaturated heterocyclic ring. Compounds of this type have frequently been described in the literature and the processes for their preparation are well-known. The precise nature of the quaternising moiety is not critical. It is only necessary that the onium groups of the potentiator be relatively small and that it have no substantial biological activity. The nature of the anion is. not critical, but should be small since the potentiator is the cation and the smaller the anion, the greater is the concentration of the cation per unit of molecular weight. Thus, among suitable compounds are the dichlorides, dibromides, or chlorobromides of any 0 the following:

1,3 -bis-(trin1ethylammonium) propane 1,3 -bisethyldimethylammonium) -p rop ane 1,3 -bis- (diethylmethylammonium) -prop ane 1,3 -bisl -methylpyrollidinium) -prop ane 1,3-bis- (4-methylmorpholinium) -propane 1 trimethylammonium 3 (4 methylmorpholinium)- propane 1-trimethylammonium-3 pyridinium-propane 1,2-bis- (trimethylammonium) -ethane 1,4-bisdiethylmethylammonium) -butane 1,3 -bistrimethyl ammonium -butane A wide variety of therapeutically active compounds having hypotensive properties has likewise been described in the literature and any of such substances can be employed. Illustrative of suitable active compounds. are

' the following:

1,6-bis-(trimethylammonium)-heXane salts 1,5-bis-(trimethylammonium)-pentane salts 1,5-bis-(N-methylpyrrolidinium)-pentane salts, such as the tartrate A I Chlorisondamine Pentamethyl-diethyl-3 -aza-pentane 1,5-diammonium-di I bromide The following description illustrates a specific, embodi rnent of the composition constituting the invention:

' 1,3-bis(trimethylammonium)propane dibromide hav ing an acute toxicity in mice of I.V. LD =83.0 milligrams per kilogram was chosen as the potentiating agent.

The effect of this compound on the blood pressure of; anesthetised dogs upon intravenous administration was determined to be:

A blood pressure fall under such test conditions, with a recovery in less than five minutes, means that the substance tested has no useful hypotensive activity since this is merely an ultra-short, transient acute response. Oral administration of such compound produces no eiiect on the blood pressure. When administered intraperitoneally in a dosage of 2.0 mg./kg. to an unanesthetised cat, the compound produced no noticeable ellects upon careful observation for evidence of ganglionic stimulation or blockade as oifered by relaxation of the nictitating mem-- brane, pupillary dilation, salivation, et cetera.

The inactive propane compound was then tested in combination with an active hypotensive compound, 1-(2- ethyl 1,2,3,4 tetrahydroisoquinolinium) 3 (trimethylammonium)propane dibromide, by injection directly into the upper third of the small intestine of anesthetised dogs, the blood pressure being recorded directly from a common carotid artery, with the following results:

Dosage, mg./kg.

Percent Duration fall in in hours Active Inactive blood greater comcompressure than pound pound The said compounds were then combined in the dosage ratios immediately above, placed in a capsule, and administered orally just prior to anesthetising and setting up dogs for recording blood pressure as above. The time required for setting up was approximately ten minutes. The results are summarized in the table below:

Dosage, rug/kg.

Percent fall in blood Duration Active Inactive pressure in hours comcompound pound In tests conducted in a similar manner with other active hypotensive agents, such as 1-[2-(naphtheneethyDpyridinium] (3 trimethylammonium)propane dibromide, using trimethylene 1,3 bis (trimethylammonium)theophyllinate, trirnethylene 1,3 bis (4 methylmorpholinium)dibromide, and, 1,3-(trimethylammonium)propane dibromide, for example, as potentiating agents, we obtained, upon oral administration in capsules, in every instance at least double the effect resulting from oral administration of the active compound alone.

Following such pharmacological investigations in animals, we have had conducted in humans a clinical evaluation of the tetrahydroisoquinolinum and naphtheneethyltion that results from the oral combination. This further supports the view that the inactive quaternary does not sensitize the organism to the therapeutic agent but rather permits better absorption of the therapeutic agent from the gastro-intestinal tract.

Among the advantages in providing a potentiated composition as herein described, as opposed to merely increasing the dosage of the active component of the composition, are the following: the potentiators are much less expensive than the therapeutic agents and there is an economic advantage; additionally, the smaller molecular weight of the simple bis-quaternary potentiators provides a high ionic concentration of quaternary groups with a relatively small weight of compound and permits preparing the tablet or oral preparation in a more practical size for administration; and, by permitting smaller doses of the therapeutically active agent, fewer side reactions are obtained than by increasing the quantity of therapeutic agent since some of the therapeutic agents produce side reactions from direct local action on the gastro-intestinal tract.

While the invention has been illustrated with reference to quaternary salts possessing hypotensive properties, we have found that other quaternary ammonium salts possessing therapeutic properties are likewise potentiated by combination with the C to C quaternaries of the type hereinbefore described. For example, cholinergic agents, such as carbamyl methylcholine, acctyl-beta-methylcholine, and neostigmine salts; and, antispasmodic agents, such as homatropine methobromide, methantheline bromide,

tricyclamol methosulfate, and tridihexethyl iodide, are increased markedly in effectiveness at reduced dosage levels. The principle of potentiation herein described is not concerned with the qualitative nature of the activity of the therapeutic quaternary, but is related to its chemical characteristics. It will thus be apparent from the foregoing that the inventive concept is of broad application and makes possible the use of substances not otherwise orally administrable in practical dosages by increasing the relative absorption of the therapeutic quaternary.

We claim:

1. A pharmaceutical composition for oral administration including one part by weight of a physiologically active, non-toxic, systemically absorbable quaternary ammonium salt in combination with between about 0.5 and 3.0 parts by weight of a substantially biologically inert bis-quaternary ammonium salt.

2. A pharmaceutical composition for oral administration including one part by weight of a non-toxic, systemically absorbable quaternary ammonium compound having hypotensive activity in combination with between about 0.5 and 3.0 parts by weight of a substantially biologically inert bis-quarternary ammonium salt.

3. The composition of claim 2 wherein the substantially biologically inert salt is of a trimethylene-bis-trimethylammonium cation.

References Cited in the file of this patent U.S. Dispensatory, 25th ed., 1955, pp. 1697-1700, 1701, 1702, 1703.

Barlow: Introduction to Chem. Pharmacology, John Wiley and Sons, N.Y., 1955, pp. 10, 11, 161-163, 179.

Hager et al.: J.A.P.A., Sci. Ed., 42:1, pp. 9, 10, 12, January 1953. 

1. A PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION INCLUDING ONE PART BY WEIGHT OF A PHYSIOLOGICALLY ACTIVE, NON-TOXIC, SYSTEMICALLY ABSORBABLE QUATERNARY AMMONIUM SALT IN COMBINATION WITH BETWEEN ABOUT 0.5 AND 3.0 PARTS BY WEIGHT OF A SUBSTANTIALLY BIOLOGICALLY INERT BIS-QUATERNARY AMMONIUM SALT. 